Oxytocin Modulation of Social Behavior

催产素对社会行为的调节

• 批准号: 10044651
• 负责人: Ismail A. Ahmed
• 金额: $ 6.72万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-02 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10044651
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease pathology; Amino Acids; Animal Model; Anus; Arts; Atomic Force Microscopy; Award; Biochemistry; Biological; Biology; Biophysics; Brain; Cell Nucleus; Cessation of life; Chemical Structure; Chemistry; Collaborations; Disease; Doctor of Philosophy; Dyes; Elderly; Engineering; Environment; Event; Exhibits; Fluorescence; Foundations; Frontotemporal Dementia; Funding; Genetic; Goals; Hydration status; In Vitro; Kinetics; Knowledge; Label; Leadership; Learning; Length; Light; Maps; Measurement; Measures; Mentorship; Methods; Microscopy; Mind; Mission; Molecular; Molecular Conformation; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neurosciences; Oxytocin; Pathogenicity; Pathology; Pathway interactions; Penetration; Peptides; Phase; Phenylalanine; Population; Positioning Attribute; Process; Property; Proteins; Protons; Research; Scientist; Seeds; Site; Social Behavior; Spectrum Analysis; Structure; Technology; Tertiary Protein Structure; Testing; Time; Training; Tryptophan; Variant; Virginia; Work; aggregation pathway; base; career; chromophore; design; disorder control; doctoral student; fluorophore; graduate student; human model; in vivo; innovation; interdisciplinary approach; interest; misfolded protein; novel; novel therapeutics; prevent; prospective; protein aggregation; protein folding; protein misfolding; single molecule; structural biology; tau Proteins; tau aggregation; tau function; tool; unnatural amino acids

Project Summary/Abstract: The Goal of this proposal is to dissect the mechanistic details surrounding the nucleation and early events of tau aggregation. Tau is a key misfolding and aggregating protein associated with both Alzheimer’s disease (AD) and frontotemporal dementia (FTD). There has been a significant increase in the number of people suffering from neurodegenerative diseases, including AD and FTD and is expected to continue to rise as there are currently no cures. While many studies have attributed the aggregation of tau as a cause of the disease, the process of nucleation and self-prorogation of tau aggregation is not well understood. One major challenge has been to determine the conformational basis of tau misfolding and aggregation due to the large size of the protein. To address this challenge, minimal sequence of 31 residues has been defined as the conformational nucleus responsible for the self-propagation of tau aggregation, thus providing a foundation for investigating the early stage of nucleation. With this observation we hypothesize that residues within this minimal sequence interact with other domains of the protein to induce aggregation at the single molecule level as well as interact with other misfolded tau molecules to seed aggregation. To test this, we propose to map these interactions in a site specific manner using minimally perturbing fluorescent unnatural amino acids to shed light on the early non-fibrillar oligomer formation and the local conformational dynamics over the course of aggregation. Innovation: In order to dissect site-specific interactions, kinetics and conformational dynamics surrounding the nucleation and early aggregation events of tau, new tools are needed. Unnatural amino acids sensitive to hydration are uniquely useful to probe aggregation because of the change in local hydration exhibited when once soluble protein becomes insoluble during aggregation. Unfortunately, current technologies such as fluorescent proteins and dyes are not ideal to study intramolecular events due to their prohibitive size. Unnatural amino acids chromophores offer the desired spectroscopic qualities in a framework that is non-perturbing to both structure and function of tau, making it ideal to study the intra- and intermolecular conformational dynamics, kinetics and interactions during tau aggregation. Together this will inform our direct knowledge to help elucidate the aggregation pathway.

项目摘要/摘要： 该提案的目的是剖析核定和早期事件的机械细节 tau聚集。 Tau是与阿尔茨海默氏病相关的关键错误折叠和汇总的蛋白质 （AD）和额颞痴呆（FTD）。人数大幅增加 患有神经退行性疾病，包括AD和FTD，预计将继续上升 目前没有治疗方法。尽管许多研究归因于tau作为疾病的原因，但 一个主要的挑战是 我们要确定tau折叠和聚集的构象基础，这是由于大尺寸的 蛋白质。为了应对这一挑战，已将31个残基的最小序列定义为构象 负责tau聚集自我传播的核，从而为研究 成核的早期阶段。通过此观察，我们假设保留在此最小序列中 与蛋白质的其他结构域相互作用，以诱导单分子水平的聚集以及相互作用 与其他错误折叠的tau分子一起以种子聚集。为了测试这一点，我们建议将这些相互作用映射到 使用最小扰动荧光非天然氨基酸的特定方式，以散发出早期的灯光 在聚集过程中，非纤维寡聚的形成和局部构象动力学。 创新：为了剖析特定地点的相互作用，动力学和构象动态 需要新工具的成核和早期聚集事件。对不自然的氨基酸对 水合对于探测聚集非常有用，因为当局部水合发生变化时 一旦固体蛋白在聚集过程中变得不溶。不幸的是，当前的技术，例如 由于禁止的大小，荧光蛋白和染料并不理想研究分子内事件。不自然 氨基酸发色团在不扰动的框架中提供所需的光谱质量 tau的结构和功能，使得研究分子内和分子间构象是理想的选择 tau聚集期间的动力学，动力学和相互作用。这将共同将我们的直接知识告知 帮助阐明聚合途径。